Studies outlined in this proposal are designed to provide a platform for research and development of new clinically translatable iPS cell lines specifically addressing the shortcomings of current iPS procedures that impede potential translation of this approach for use in the clinic. Induction of pluripotent status in somatic cells by directed reprogramming in-vitro, induced pluripotent stem (iPS) cells, is of great potential significance for the generation of disease and patient specific cell lines and cell therapy (1,2,3). Although quite promising and revolutionary, to date iPS techniques share several main shortcomings which collectively impede potential translation of this approach for use in the clinic. Our long-term goal (Phase II and beyond) is to develop, tools, and cell lines that allow translation of iPS cells into therapies for the clinic. The specific hypothesis behind the proposed research is that improved more clinically translatable iPS procedures such as the use of small molecule inducers of iPS signal transduction pathways, can be devised streamlining development of "clinically translatable" human iPS cell lines. Accomplishing the specific aims outlined in this proposal will provide the foundation required to assess the possibility of generation of Human iPS cell lines by clinically relevant methodologies, eliminating the current impediments for translation of iPS cells into the clinic. In this Phase I feasibility demonstration project we plan to further characterize "pluripotency" of previously developed human chemically induced iPS (CiPSTM) cells at the molecular, cellular levels including studies in SCID mouse models. Furthermore, in preparation for further refinements of the CiPS methodology (Phase II), we will adapt their cultivation and derivation to the Cell Matrix ArraysTM (http://www.dnamicroarray.com/cell_matrix_arrays.htm) PUBLIC HEALTH RELEVANCE: Studies outlined in this proposal are designed to provide a platform for research and development of new clinically translatable induced pluripotent stem (iPS) cell lines specifically addressing the shortcomings of current iPS procedures that impede potential translation of this approach for use in the clinic. We propose to eliminate the need for genetic alterations of iPS cells, increase the efficiency of the process, and develop clinically applicable identification methodologies for iPS cells. Human iPS cells hold great potential for the generation of disease and patient specific cell lines, cell therapies and tissue regeneration, benefiting the current unmet need for patient customized cell lines that could be used for treatment of life threatening diseases and injuries. Accomplishing the specific aims outlined in this proposal will provide the foundation required to assess the possibility of generation of Human iPS cell lines by clinically relevant methodologies, eliminating the current impediments for translation of iPS cell lines into the clinic.